ABSTRACT The carbohydrate synthesis is lagging far behind the current status of peptide and nucleotide synthesis. This is not due to the lack of importance. In fact, carbohydrates are ubiquitous and play a vital role in many important biological events. The development of efficient and selective chemical methods for the synthesis of carbohydrates and their analogues is necessary for the understanding of the specific roles of carbohydrates and for therapeutic development. Current carbohydrate synthesis requires extensive training and knowledge. One has to think outside the box for transformative solutions that can enable non-experts in the biomedical community to study carbohydrate structure and function. The two most essential issues in carbohydrate synthesis are stereoselective glycosidic bond formation and differentiation of hydroxyl groups. In this proposal, we will develop catalytic methods to address both issues and streamline the assembly of oligosaccharides. In Aim 1, we propose to site-selectively functionalize hydroxyl groups in various monosaccharides in a predictable, general, and systematic manner. These transformations will be used for streamlining the synthesis of carbohydrate building blocks. Working models that can predict the site-selectivity in diverse carbohydrates will be established with the help from computational chemists. In Aim 2, we propose to develop novel transition metal-catalyzed cross-coupling glycosylation (CCG) to construct the glycosyl carbon-oxygen bond guided by density functional theory calculations and published literature on cross-coupling reactions. The CCG will allow us to assemble the stereochemically defined benchtop stable glycosyl donors and novel glycosyl acceptors stereospecifically without any manipulation after glycosylation. Our proposed glycosylation methods are innovative because they don?t involve the formation of the oxocarbenium ion, which often makes the current glycosylation methods not completely stereoselective. The glycosyl donors and acceptors for CCG will be derived from naturally occurring monosaccharides. Similar to all chemical methods, the CCG can also be used for the synthesis of carbohydrate analogues. In Aim 3, we will demonstrate the efficiency of the proposed methods in several iterative syntheses of bioactive bacterial and human glycans. The iterative synthesis only involves one step of activation of glycosyl donors or acceptors and one step of CCG for the addition of any monosaccharide unit. Glycosyl donors and acceptors without protecting the nonparticipating hydroxyl groups can also be employed because of the unique feature of the CCG. The above proposed aims are significant because they will yield readily available tools for anyone in the biomedical community including non-experts to study carbohydrate structures and functions. The successful development of the proposed methods will place the oligosaccharide synthesis close to the modern status of oligopeptide and oligonucleotide synthesis.